PANCREATIC CANCER Canada is proud to support the Pancreas Cancer Screening Study at Toronto's Princess Margaret Hospital and a Trial of Stereotactic Body Radiotherapy (SBRT) Boost During Concurrent Gemcitabine-Based Chemoradiotherapy for Locally Advanced Pancreatic Cancer at Ottawa General. Below are descriptions of each study.
Currently there is no proven method of early detection available and few treatment options available. It is our hope that we can help make early detection of the pancreas a reality and offer an alternative treatment to those patients who have been diagnosed with early stages of pancreatic cancer yet there tumor is deemed inoperable.
1) Pancreas Cancer Screening Study - led by Dr. Steven Gallinger and Dr. Malcolm Moore
About the Study
Funding generated from this project will support continued research into the early detection of pancreatic cancer because early detection is proven to be associated with a better prognosis or outcome. Unfortunately, the majority of pancreatic cancer cases are diagnosed in the late stages when the cancer has metastasized to surrounding organs. This is due to the location of the pancreas and the lack of definitive symptoms. There is currently no proven method of early detection available. Until researchers can discover a screening test for this lethal disease, it will remain a silent killer.
The Pancreas Cancer Screening Study started at Mount Sinai Hospital and the University Health Network in Toronto began in 2003. The goal of this study was to determine the effectiveness of MRI (magnetic resonance imaging) and abdominal ultrasound for the early detection of pancreatic cancer. Researchers look specifically for the most common type of pancreatic cancer, called adenocarcinoma. Each participant is asked to return annually for a transabdominal ultrasound and magnetic resonance imaging (MRI) of the pancreas and to provide a blood sample for future biomarker studies. As of January 2009, the use of abdominal ultrasound was discontinued as findings proved that ultrasound did not detect potentially important pancreas lesions (abnormal changes) that had been identified on MRI.
Participants in this study consist of groups considered to be at a higher risk.
These participants include those with BRCA1, BRCA2, P16, MMR gene mutations, familial atypical multiple mole melanoma (FAMMM), Peutz-Jeghers Syndrome (PJS), those with hereditary pancreatitis, and most importantly, those with a specific family history of pancreas cancer - 2 or more members from the same side of a family - familial pancreas cancer (FPC).
To Date
Over 240 participants have enrolled and two cases of pancreatic adenocarcinoma have been identified.
One of these patients had surgery and is alive and well two and a half years later. The other patient was diagnosed with a more advanced stage of the disease and has since passed away. Although the purpose of our screening study is to detect new pancreas adenocarcinomas, other cancer types that have been found during the study include a pancreatic neuroendocrine tumour, an ovarian cancer, a stomach tumour, and three kidney cancers. Benign pancreas lesions have been found in 15 patients and pancreas cysts have been found in 79 patients.There is currently no consensus among surgeons and researchers when these benign pancreas lesions should be surgically removed; however all of these patients are being followed closely.
*At the moment. new enrollment is closed.
The Future
The Pancreatic Cancer Screening Study is ongoing and we hope to enroll more participants in the future. Together, with our other concurrent research, the objective of which is to identify environmental and genetic risk factors of pancreas cancer, we hope to identify the Familial Pancreas Cancer (FPC) gene(s) and genetic biomarkers which are urgently needed for disease detection and improved clinical management of these patients. Once a genetic test for pancreas cancer is available, we will be able to screen the blood samples of the current participants to determine whether we are screening the correct cohort of individuals.
This study will lead to a better understanding of how pancreatic cancer can be detected at the earliest possible stage for individuals who are at increased risk for developing this disease.
Detecting cancer early may also mean it is more likely to be curable which is the ultimate goal of this research.
Importance of Study
Many people with pancreas cancer report having a family history of the disease. Identifying the FPC gene(s) is of critical importance in understanding both the heredidtary and more common sporadic forms of the disease. Moreover, the availability of a genetic blood test to identify people at increase risk for the disease will be instrumental in developing novel and cost-effective screening tests.
This research study is part of a larger consortium of centres with an interest in FPC and support for this group (called The Pancreas Cancer Genetic Consortium, PACGENE) has been obtained by the US National Institutes of Health for the past 6 years. As a byproduct of our participation in PACGENE, there has developed expertise in understanding a new form of genetic variation called copy number variation (CNV), and PMH/OCI is applying this knowledge to search for the FPC gene(s) using technology available to our laboratories in Toronto.
Which other PACGENE centres participating in the study?
Mayo clinic, Rochester Minnesota / Creighton University, Nebraska / Johns Hopkins University, Maryland / Karmanaos Cancer Institute, Michigan / MD Anderson Cancer Center, Texas / Dana Farber Cancer Insitute, Boston MA
For more information about the pancreas cancer screening study, please e-mail ABorgida@mtsinai.on.ca or call toll free at 1-877-586-1559 and leave a message.
Each year a generous donation is made by Pancreatic Cancer Canada /The Dick Aldridge Pancreatic Cancer Foundation to support this important research, click here to read - (http://www.pmhf-uhn.ca/Pages/NewsAndMedia/NewsStory.aspx?s=384)
2010 SCREENING STUDY BUDGET
PERSONNEL
A Research Assistant is required to coordinate this study. A second Research Assistant (50% effort) is required to maintain our population-based recruitment of newly diagnosed cases of pancreatic cancer to identify relatives who are eligible for the early detection study.
Research Assistant: (1.0 FTE)
$36,000 + 22% benefits = $43,920
Research Assistant: (0.5 FTE)
0.5 x ($40,000 + 22% benefits) = $24,400
SUPPLIES AND SERVICES
Blood Draws (based on 15 new enrolled participants/year)
$25/person x 15 participants = $375/year
Blood Processing and Lymphocyte Storage
Peripheral blood lymphocytes will be extracted from whole blood in the Biospecimen Repository at Mount Sinai Hospital. Serum will be extracted and stored as 1ml aliquots. 260 screening participants have donated blood samples which are currently being stored for future biomarker and genetic studies in high risk families.
Procession: 15 cases/yr at $15/case = $225/yr
Storage: $300/month x 12 months/year = $3600/year
Tissue Sample Requests
We will request tissue samples to look for genes and/or other biological markers that affect the risk of developing cancer, and for early detection = $3000/yr.
Parking Reimbursement for Patients
We also provide some reimbursement for the parking costs incurred by participants on their appointment days. 15 participants/year x $10 parking = $150.
TOTAL: $75,670
2) Trial of Stereotactic Body Radiotherapy (SBRT) Boost During Concurrent Gemcitabine-Based Chemoradiotherapy for Locally Advanced Pancreatic Cancer - led by Dr. John Pantarotto
Of the hundreds of Canadians diagnosed with pancreatic cancer each year, a significant proportion will present with disease confined to the pancreas but deemed technically inoperable. Thus far, no local therapy of any kind provides the same option for cure in this subset of patients; and thus the current regimens of chemotherapy with or without conventional radiotherapy are palliative.
The development of a new, highly-focused radiation technique called Stereotactic Body Radiotherapy (SBRT) may provide a non-surgical and non-invasive way of managing some patients with pancreatic tumors. SBRT delivers ultra-high doses of radiation using modern linear accelerators or dedicated units such as CyberKnife® that focus several small beams on a specific point in the body.
This study will combine gemcitabine-based chemotherapy with a strategy of radiation delivery that treats the surrounding lymph nodes to standard doses of radiation but the primary tumor will receives an ultra-high dose “boost” delivered on a CyberKnife® unit. The goal is to establish a relationship between SBRT radiation boost dose and side effects patients may experience. The study will provide the groundwork for future studies that compare SBRT to traditional therapies for locally advanced pancreatic cancer.
Rationale for the study:
Pancreatic cancer is the fourth leading cause of cancer death in Canada (Canadian Cancer Statistics, 2009). Thus far, complete surgical resection of early disease is the only treatment modality that gives any real chance for cure. The majority of patients do not present with early disease: approximately 35-40% of pancreatic cancer patients present with locally advanced, inoperable disease due to invasion of critical vessels or surrounding organs.
Alternative local treatments to eradicate disease confined to the pancreas are limited. Conventional radiotherapy, where small doses of daily radiation are given over weeks and usually in the setting of concurrent chemotherapy, is limited by the tolerance of surrounding organs such as bowel, stomach, spinal cord and kidneys. It is difficult to
deliver a significant dose to the pancreas without causing fairly severe side effects to the patient and unfortunately, local failure (i.e. within the radiation field) after a course of chemo-radiotherapy is common (30-50%, Willet et al).
Stereotactic body radiotherapy (SBRT) is a new technique that allows for ultra-high doses of radiation to be delivered to small areas with precision not previously possible using older equipment. The CyberKnife® Robotic Radiosurgery System (Accuray, Sunnyvale California, USA) is a radiation unit specifically designed to focus beams of radiation accurately anywhere in the body. It is able to track, detect and correct for any tumor movement during treatment by using a sophisticated image guidance system. A robotic manipulator moves the radiation source to multiple positions resulting in several small beams overlapping on the tumor. Metal seeds (fiducials) are required to allow the software to track the actual position of the tumor. For tumors in the pancreas an endoscopic ultra-sound (EUS) guided approach for placing these seeds prior to treatment is safe, effective and avoids having to gain access via a needle through the abdominal wall (Sanders et al, 2010).
SBRT may reduce the local failure rates associated with current treatment strategies in locally advanced pancreatic cancer. Results of SBRT alone are encouraging (Koong et al. 2004, 2005) with the ability to shrink or stabilize the primary pancreatic tumor in 90% of cases when using a single large fraction of SBRT radiation (25 Gy). The regional and distant failure rates remained high and overall survival was no better than other trials investigating standard chemo-radiation. Toxicity with this large boost dose was also quite high.
For this study it is felt that a combined approach utilizing gemcitabine-based chemotherapy in combination with conventional radiotherapy to the pancreatic nodal basin is required. As such we propose integrating SBRT as a boost, aimed only at the primary tumor itself and given in conjunction with 4 weeks of “conventional” radiotherapy. We hypothesize that the increased accuracy of CyberKnife® will allow for the safe delivery of ultra-high doses of radiation to the primary pancreatic tumor and not interfere with the delivery of gemcitabine-based chemoradiotherapy.
The Ottawa Hospital takes delivery of only the third CyberKnife® unit in Canada in July 2010, with an expectation of entering clinical use by October 2010. Stereotactic radiotherapy has been delivered to tumors within the brain in Ottawa for over 15 years. Similarly, a lung tumor SBRT program began in October 2008, and has quickly grown to become one of the largest in Canada. Liver SBRT treatments commenced in 2009, and plans are in place to expand to several other body sites with the arrival of CyberKnife®. Endoscopic placement of fiducials is a technique unique to one individual at The Ottawa Hospital and hence Dr. Chatterjee will be assessing all patients in this regard.
Financial Reporting:
Primary source of study cost will be Clinical Research Assistant (CRA) time, fiducial markers and diagnostic imaging scans.
CRA: Costs below have NOT been confirmed with clinical trial management but represent figures proposed for recent cooperative group trials.
Informed consent: $150/patient
CRA Assessments ($50 per hour)
Pretreatment, on treatment, 1 month after then q3 months x2 years = 6.5 hours x $50 = $325
Total CRA Costs: 30 patients x ($150 + 325) = $14,250
Fiducial marker cost
$75 per fiducial, 4 per tumor = $300 per patient
For 30 patients: $9000 ** Some patients will require extra fiducial - add 25%
Fiducial cost: $11,250
Diagnostic Imaging cost
MRI pre-treatment is standard of care therefore cost is 0.
Post-radiation CT scans at 3 months, 12 months (at $437.86 per CT with contrast) is above standard of care $875.72 per patient
For 30 patients: $26,271.60
Clinical Trial Administration start up fee $1500
Total Cost: $53,271.60
Goals/Objectives:
To determine the maximum tolerated radiation dose (MTD) for pancreatic tumors using a stereotactic body radiotherapy boost technique. Secondary objectives will be to i) assess the rate of significant toxicities, ii) rate of tumor response following treatment iii) establish dose-volume relationship for various organs and toxicity.
Methodology:
Eligible patients will consist of those with new or recurrent, biopsy proven adenocarcinoma with disease limited to the pancreas. All patients are to be assessed by the hepatopancreatobiliary (HPB) surgical oncology team or presented at HPB rounds and deemed technically or medically inoperable. Maximum tumor size will be 6 cm as per pre-treatment MRI and may be anywhere within the pancreas. Enlarged peri-pancreatic lymph nodes are acceptable for study entry however other abdominal lymphadenopathy or distant metastases are not. Other inclusion criteria include KPS>60, life expectancy>3 months, Child's A liver score, and hemoglobin>90. Patients with previous radiotherapy to the abdomen or contraindications to radiotherapy will not be allowed on study.
Fiducial marker placement within the tumor (total of 3-5) will be done via endoscopic ultra-sound guided placement where possible. Patients brought to the OR and deemed inoperable at that time may have fiducials placed at the time of the open procedure.
Induction chemotherapy will be given with gemcitabine-based chemotherapy for Weeks 1 and 2. (An application for erlotonib as a secondary agent to be given with gemcitabine has been requested and is pending). Radiotherapy would commence on Week 4 with Week 3 used as a break. SBRT on CyberKnife® will be given on 3 days of Week 4 (M, W, F) with no concurrent chemotherapy given. Conventional chemo-radiotherapy (gemcitabine) commences on Week 5 to a dose of 45 Gy in 20 fractions using intensity-modulated radiotherapy planning and delivery.
The experimental variable is the dose given in each of the 3 SBRT fractions in Week 4.
Individual cohorts of dose will be established. The starting dose will be 6Gy in 3 fractions. Dose escalation of 3Gy for each addition cohort (i.e. 18Gy in 3, 21Gy in 3, etc.) Maximum dose level will be 30Gy in 3.
Dose limiting toxicities will be based on NCI Common Toxicity Criteria for liver, small bowel, kidney, lung, heart, esophagus and stomach. A 5+5 design will be used for this Phase I dose escalation trial. This design allows for a maximum 40% of patients within a cohort of experiencing a DLT. Anything higher than 40% will terminate escalation and expand a lower dose level if only 5 patients have been enrolled at that level. This design will also increase the ability to describe the toxicity at each dose level.
Weekly gemcitabine-based chemotherapy will continue after chemo-radiotherapy for a minimum of 3 months, up to the discretion of the medical oncologist.
Follow up will consist of assessments by the radiation oncologist, medical oncologist and CRA. Patient will be seen daily while on SBRT treatment, weekly when on conventional chemo-radiotherapy, then 1 week post treatment, 1 month post treatment, then 3months thereafter. CT scans will be obtained at 6 monthly intervals as part of standard of care in the management of pancreatic cancer, but 3months in year 1 for this trial.
Total patients needed: Assuming no expansion required at any dose level in the 5+5 design, 30 patients would be required. More may be required but this is impossible to predict using this Phase I design. The proposal is based on 30 patients, with the understanding that not all dose levels may be possible.
3. The Researchers
Malcolm J Moore, MD
Professor of Medicine and Pharmacology in the Department of Medical Oncology and Hematology at Princess Margaret Hospital, University of Toronto and a Senior Scientist in the Division of Experimental Therapeutics at the Ontario Cancer Institute. He is chair of the GI Cancer Program at PMH and was recently appointed Chair of the GI committee for National Cancer Institute of Canada [NCIC]. Dr Moore is Director of the Drug Development Program at PMH and heads the PMH Phase II Consortium, an alliance of 3 hospitals, PMH, Hamilton and London Regional Cancer Centres that won a contract with NCI ensuring access to new NCI anti-cancer drugs
Princess Margaret Hospital
5th Floor Rm 5-205
610 University Ave
Toronto, Ontario
Canada M5G 2M9
Email -
Malcolm.Moore@uhn.on.ca
Senior Scientist
Division of Applied Molecular Oncology
Ontario Cancer Institute (OCI)
Clinical Studies Resource Centre Member
Ontario Cancer Institute (OCI)
Research Interests
His major interest over the past 10 years has been innovative drug development for cancer therapy. He has been a principal investigator for many phase I, II and III studies in gastrointestinal and genitourinary cancer supported by NCI, NCIC and the pharmaceutical industry. Areas of focus for new drug development are signal transduction inhibitors, modulation of gene expression and angiogenesis. He has been instrumental in the development of a number of agents that have subsequently been approved for clinical usage such as mitoxantrone in hormone refractory prostate cancer and gemcitabine in both pancreatic and urothelial cancer. Dr Moore has 90 peer reviewed publications and has given over 100 invited lectures.
Malcolm Moore is a DOE specialist, Master Black Belt and Six Sigma Analyst with SAS UK in their JMP software business unit.
Additional Appointments
Co Chair in Prostate Cancer Research, Princess Margaret Hospital
Chair of the National Cancer Institute of Canada GI cancer disease site
Professor, Department of Medicine and Pharmacology, University of Toronto
